FDA Approves New U.S. Labeling for ISENTRESS® (raltegravir) to Include 240-Week Results from STARTMRK Study of ISENTRESS Containing Regimen in Previously Untreated HIV-1 Infected Adult Patients


July 1, 2013 4:05 pm ET

Merck (NYSE: MRK), known as MSD outside the United States and Canada,
announced today that the U.S. Food and Drug Administration (FDA) has
approved new labeling for ISENTRESS® (raltegravir)
Film-coated Tablets, Merck’s integrase inhibitor for the treatment of
HIV-1 infection in adult patients as part of combination HIV therapy.
The updated prescribing information now includes 240-week results from
the STARTMRK study, the longest double-blind Phase III non-inferiority
study evaluating an integrase inhibitor in treatment-naïve adult
patients with HIV-1 infection. The results show that the regimen
containing ISENTRESS in combination therapy demonstrated long-term viral
suppression and a greater immunologic response than the
efavirenz-containing regimen, as well as a proven, long-term safety and
tolerability profile through 240 weeks in previously untreated
(treatment-naïve) adult HIV-1 infected patients.

ISENTRESS is an integrase inhibitor indicated in combination with other
antiretroviral (ARV) agents for the treatment of HIV-1 infection in
adults. This indication is based on analyses of plasma HIV-1 RNA levels
in three double-blind controlled studies of ISENTRESS. Two of these
studies were conducted in clinically advanced, three-class ARV
[non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside
reverse transcriptase inhibitor (NRTI), protease inhibitor (PI)]
treatment-experienced adult patients through 96 weeks and one was
conducted in treatment-naïve adults through 240 weeks.

The use of other active agents with ISENTRESS (raltegravir) is
associated with a greater likelihood of treatment response.

Severe, potentially life-threatening and fatal skin reactions have been
reported with ISENTRESS. Additionally, during the initial phase of
combination ARV treatment, immune reconstitution syndrome may occur.
(See Important Selected Safety Information below.)

“As the care of HIV evolves, ISENTRESS continues to be an important
treatment option for adult patients with HIV-1,” said Jürgen Rockstroh,
M.D., University of Bonn, Bonn-Venusberg, Germany. “These 240-week
results are important for physicians to consider when initiating
treatment with ISENTRESS in combination therapy in treatment-naïve adult
patients with HIV-1.”

“Merck has been at the forefront of HIV research for close to 30 years.
The discovery of ISENTRESS and its clinical development program are a
testament to Merck’s long-term commitment to the research and
development of medicines for HIV,” said Daria Hazuda, Ph.D., vice
president of Early Development and Discovery Sciences Research for
infectious diseases, Merck.

STARTMRK study design

STARTMRK was a multi-center, double-blind, randomized,
active-controlled, Phase III non-inferiority study. In the study, 563
previously untreated HIV-1 infected adult patients with HIV-1 RNA
greater than 5,000 copies/mL received either 400 mg ISENTRESS orally
twice daily (n=281) or 600 mg efavirenz orally once daily (n=282), each
in combination with tenofovir/emtricitabine. The primary endpoint of the
study was a reduction in HIV-1 viral load to less than 50 copies/mL at
week 48. Secondary endpoints included ARV activity, as measured by the
proportion of patients achieving HIV-1 viral load to less than 50
copies/mL at 96 weeks, as well as achieving viral load less than 400
copies/mL and change from baseline in CD4 cell count, both measured at
48 and 96 weeks. Pre-specified exploratory endpoints also included the
proportion of patients achieving HIV-1 viral load to less than 50
copies/mL at 240 weeks, as well as change from baseline in CD4 cell
count at 240 weeks. Safety was evaluated throughout the study period.
Merck presented the 240-week STARTMRK study results for the first
time at AIDS 2012 in Washington, D.C. and the results were subsequently
published in Journal of Acquired Immune Deficiency Syndromes (JAIDS) in
May 2013.

ISENTRESS (raltegravir) in combination therapy shows long-term
efficacy in previously untreated adult HIV-1 patients through 240 weeks

In the STARTMRK trial, the regimen containing ISENTRESS was non-inferior
to the regimen containing efavirenz at reducing HIV-1 viral load to
undetectable levels (less than 50 copies/mL) at 240 weeks. At the study
entry, the geometric mean baseline plasma HIV-1 RNA for patients was
over 100,000 copies/mL (103,205 copies/mL for those on a regimen
containing ISENTRESS (raltegravir) and 106,215 copies/mL for patients on
a regimen containing efavirenz). Results for the 240-week analysis
showed long-term viral suppression (HIV-1 RNA less than 50 copies/mL)
for patients on the regimen containing ISENTRESS of 66 percent and 60
percent for the regimen containing efavirenz [treatment difference of
6.6 percent of patients with 95 percent confidence interval (CI): -1.4
percent, 14.5 percent].

The regimen containing ISENTRESS demonstrated a greater immunologic
response than the regimen containing efavirenz at 240 weeks. Patients on
the regimen containing ISENTRESS had a mean baseline CD4 cell count of
219 cells/mm3 compared to 217 cells/mm3 for
patients on the regimen containing efavirenz. From study entry to week
240, patients on the regimen containing ISENTRESS had a mean baseline
increase in CD4 cell count of 295 cells/mm3 versus 236
cells/mm3 for patients on the regimen containing efavirenz.

Safety and tolerability profile for ISENTRESS (raltegravir) through
240 weeks in STARTMRK

In the STARTMRK trial, through 240 weeks, there was a low incidence of
drug-related adverse reactions of moderate to severe intensity that
occurred in greater than or equal to 2 percent of patients treated with
ISENTRESS. These adverse drug reactions as compared to efavirenz were
insomnia (4 percent, in both arms), headache (4 percent versus 5
percent), nausea (3 percent versus 4 percent), fatigue (2 percent versus
3 percent) and dizziness (2 percent versus 6 percent). “Moderate”
reactions were defined as discomfort enough to cause interference with
usual activity. “Severe” reactions were defined as incapacitating with
inability to work or do usual activity.

Patients on the regimen containing ISENTRESS also demonstrated a lower
treatment discontinuation rate due to clinical adverse reactions versus
patients on the regimen containing efavirenz through 240 weeks (5
percent versus 10 percent, respectively). Additionally, ISENTRESS in
combination therapy had less effect on lipids [total, low-density
lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol] and
triglycerides fasting serum lipids at week 240, as shown in the table

Lipid Values, Mean Change from Baseline at Week 240







Twice Daily + Emtricitabine (+)


N = 207



Efavirenz 600 mg

At Bedtime + Emtricitabine (+) Tenofovir

N = 187


Change from

Baseline at

Week 240


Change from

Baseline at

Week 240






Week 240




Mean Change







Week 240




Mean Change




  96   106   10     93   118   25


38 44 6 38 51 13


159 175 16 157 201 44



    128   130   2     141   178   37  

*Fasting (non-random) laboratory tests at Week 240.


N = Total number of subjects per treatment group with at least
one lipid test result available. The analysis is based on all
available data.

If subjects initiated or increased serum lipid-reducing agents,
the last available lipid values prior to the change in therapy
were used in the analysis. If the missing data was due to other
reasons, subjects were censored thereafter for the analysis.

At baseline, serum lipid-reducing agents were used in 5% of
subjects in the group receiving ISENTRESS (raltegravir) and 3% in
the efavirenz group. Through Week 240, serum lipid-reducing agents
were used in 9% of subjects in the group receiving ISENTRESS and
15% in the efavirenz group.


Important Selected Safety Information

ISENTRESS (raltegravir) does not cure HIV-1 infection or AIDS.

Severe, potentially life-threatening and fatal skin reactions have been
reported. This includes cases of Stevens-Johnson syndrome,
hypersensitivity reaction and toxic epidermal necrolysis. Immediately
discontinue treatment with ISENTRESS and other suspect agents if severe
hypersensitivity, severe rash, or rash with systemic symptoms or liver
aminotransferase elevations develop and monitor clinical status,
including liver aminotransferases closely.

Immune reconstitution syndrome can occur, including the occurrence of
autoimmune disorders with variable time to onset, which may necessitate
further evaluation and treatment.

Co-administration of ISENTRESS with drugs that are strong inducers of
uridine diphosphate glucuronosyltransferase (UGT1A1) may result in
reduced plasma concentrations of raltegravir. Rifampin, a strong
inducer of UGT1A1, reduces plasma concentrations of ISENTRESS.
Therefore, the dose of ISENTRESS for adults should be increased to 800
mg twice daily during coadministration with rifampin. There are no data
to guide co-administration of ISENTRESS with rifampin in patients below
18 years of age.

The most commonly reported (≥2%) drug-related clinical adverse reactions
of moderate to severe intensity in treatment-naïve adult patients
receiving ISENTRESS compared with efavirenz were insomnia (4% vs 4%),
headache (4% vs 5%), nausea (3% vs 4%), fatigue (2% vs 3%), and
dizziness (2% vs 6%), respectively. Intensities were defined as follows:
Moderate (discomfort enough to cause interference with usual activity);
or Severe (incapacitating with inability to work or do usual activity).

Grade 2 to 4 creatine kinase laboratory abnormalities were observed in
patients treated with ISENTRESS (raltegravir). Myopathy and
rhabdomyolysis have been reported. Use with caution in patients at
increased risk of myopathy or rhabdomyolysis, such as patients receiving
concomitant medications known to cause these conditions.

Rash occurred more commonly in treatment-experienced subjects receiving
regimens containing ISENTRESS plus darunavir/ritonavir, compared to
subjects receiving ISENTRESS without darunavir/ritonavir or
darunavir/ritonavir without ISENTRESS. However, rash that was considered
drug-related occurred at similar rates for all three groups. These
rashes were mild to moderate in severity and did not limit therapy;
there were no discontinuations due to rash.

ISENTRESS should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. To monitor maternal-fetal
outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to
register patients by calling 1-800-258-4263.

About ISENTRESS (raltegravir)

ISENTRESS is Merck’s integrase inhibitor for the treatment of HIV-1
infection in adult patients and pediatric patients ages 2 years and
older and weighing at least 10 kg as part of combination HIV therapy.
ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA
by the integrase enzyme and has demonstrated rapid antiviral activity.
Inhibiting integrase from performing this essential function limits the
ability of the virus to replicate and infect new cells. ISENTRESS is now
approved in combination therapy in more than 76 countries for use in
treatment-naïve adult patients with HIV-1 and in more than 110 countries
for use in treatment-experienced adult patients with HIV-1. ISENTRESS,
in combination therapy, for use in pediatric patients with HIV-1 has
also been approved for use in 33 countries. Merck is continuing to move
forward with filings in additional countries around the world.

To assist patients taking ISENTRESS, Merck offers the SUPPORT™ program,
which provides personal support and patient advocacy regarding
individual reimbursement issues. For more information about the SUPPORT™
program, please visit www.merckhelps.com
or call 1-800-850-3430.

About Merck

Today’s Merck is a global healthcare leader working to help the world be
well. Merck is known as MSD outside the United States and Canada.
Through our prescription medicines, vaccines, biologic therapies, and
consumer care and animal health products, we work with customers and
operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to
healthcare through far-reaching policies, programs and partnerships. For
more information, visit www.merck.com
and connect with us on Twitter,
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Forward-Looking Statement

This news release includes “forward-looking statements” within the
meaning of the safe harbor provisions of the United States Private
Securities Litigation Reform Act of 1995. These statements are based
upon the current beliefs and expectations of Merck’s management and are
subject to significant risks and uncertainties. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.

Risks and uncertainties include but are not limited to, general industry
conditions and competition; general economic factors, including interest
rate and currency exchange rate fluctuations; the impact of
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United States and internationally; global trends toward health care cost
containment; technological advances, new products and patents attained
by competitors; challenges inherent in new product development,
including obtaining regulatory approval; Merck’s ability to accurately
predict future market conditions; manufacturing difficulties or delays;
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dependence on the effectiveness of Merck’s patents and other protections
for innovative products; and the exposure to litigation, including
patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking
statement, whether as a result of new information, future events or
otherwise. Additional factors that could cause results to differ
materially from those described in the forward-looking statements can be
found in Merck’s 2012 Annual Report on Form 10-K and the company’s other
filings with the Securities and Exchange Commission (SEC) available at
the SEC’s Internet site (www.sec.gov).

Please see Prescribing Information for ISENTRESS at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf
and Patient Information for ISENTRESS at

ISENTRESS® is a registered trademark of
Merck & Co., Inc., Whitehouse Station, N.J., USA

INFC-1083968-0000 7/1

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